The aim of this study is to investigate selected areas of the neurobiology of depression. Depressed patients free of psychotropic medications for at least two weeks are evaluated, diagnosed and symptoms rated on the 4-East Clinical Research Unit of the NIH Clinical Center. During the past year we have attempted to assess neurotransmitter function in depression by measuring levels of amine and amine metabolites in plasma and cerebrospinal fluid in depressed patients and normal controls. We have observed higher levels of circulating plasma norepinephrine in unipolar patients with DMS-III diagnosed melancholia in comparison to controls. We have also found that melancholic patients have lower levels of CSF HVA and DOPAC than nonmelancholic depressed patients. These data suggest activation of the sympathetic nervous system and diminished CNS dopaminergic system function, respectively, in patients with melancholia. We have also studied underlying mechanisms involved in the activation of the hypothalamic-pituitary-adrenal (HPA) axis, a disturbance found in many depressed patients. We have observed that nonsuppression to the dexamethasone suppression test (DST) is associated with higher levels of plasma norepinephrine and with higher levels of CSF MHPG. We have also found that low levels of the brain peptide, somatostatin, are associated with DST nonsuppression. We have also investigated clinical and biochemical effects of tetrahydrobiopterin, a pterin cofactor, in a pilot study of depressed patients.